CNNM4 (cyclin and CBS domain divalent metal cation transport mediator 4) is a membrane protein that functions as a magnesium transporter, facilitating Mg²⁺ efflux from cells 1. In the colon, CNNM4 mediates transcellular absorption of Mg²⁺ alongside TRPM6/7 channels 2. The protein contains a CBS domain that is critical for its function, as missense variants p.(Gly492Cys) and p.(Gly492Asp) in this domain reduce protein stability and significantly impair Mg²⁺ extrusion activity 3. CNNM4 regulates intracellular Mg²⁺ homeostasis through interaction with phosphatase of regenerating liver (PRL), which can inhibit CNNM4-dependent Mg²⁺ efflux 1. This regulation links Mg²⁺ homeostasis to energy metabolism via AMPK/mTOR signaling pathways 1. Pathogenic variants in CNNM4 cause Jalili syndrome, an autosomal recessive disorder characterized by cone-rod dystrophy and amelogenesis imperfecta 34. Clinically, CNNM4 appears to function as a tumor suppressor, as its expression shows an inverse relationship with colon cancer malignancy, and its deletion promotes malignant progression of intestinal polyps in mouse models 1. The protein may also play protective roles in other cancers by inhibiting cell migration and invasion 5.